1. Field of the Invention
This invention relates to a hemoglobin-albumin complex, and an artificial plasma expander and an artificial oxygen carrier containing the complex, particularly to a hemoglobin-albumin complex (heterocluster) having hemoglobin and albumin bound via a crosslinker, and an artificial plasma expander and an artificial oxygen carrier containing the complex.
2. Related Art
One of the important roles of blood is oxygen transport. Oxygen is constantly supplied to body tissue cells by hemoglobin (hemeprotein having heme as the active center and a molecular weight of about 64,500) in a red blood cell contained in blood binding oxygen in the lung and dissociating oxygen in peripheral tissue.
When a large amount of bleeding from a human body occurs due to a disaster, accident or the like, oxygen transport within a body needs to be recovered/maintained by blood transfusion. In many medically advanced countries, the blood donation/transfusion system has been improved, and the risk involved in blood transfusion such as viral infection is considerably low.
However, when a red blood cell is administered, confirmation of blood type (crossmatching) needs to be done in advance. Also, the risk of being infected by an unknown virus cannot be completely eliminated. Moreover, since the storage period of a red blood cell is as short as 3 weeks at 4° C., the concern is that a sufficient amount of blood for transfusion cannot be ensured when a large scale disaster occurs. Furthermore, it is anticipated that in the future, along with declining birthrate and aging population, the population of blood donor generation decreases, and a stable supply of blood for transfusion becomes difficult to obtain.
In addition, currently, although development of substitutes for blood components other than a red blood cell (e.g., plasma protein) has progressed, development of an artificial red blood cell (oxygen carrier) as a substitute for a red blood cell has been delayed. Thus, if an artificial red blood cell (oxygen carrier) as a substitute for a red blood cell is developed, development of artificial blood would also be largely developed.
Under such a circumstance, development of an artificial oxygen carrier (artificial red blood cell) which has no blood type (is administrable to a human with any blood type), has no risk of viral infection and the like, is storable for a long period, and is usable anytime needed, has internationally been expanded.
However, in the United States, as an artificial oxygen carrier, the intramolecular crosslinked hemoglobin having hemoglobin intramolecular crosslinked (e.g., see Patent Document 1), the hemoglobin polymer having human hemoglobin bound via a crosslinker (e.g., see Patent Document 2), the hemoglobin polymer having bovine hemoglobin bound via a crosslinker (e.g., see Patent Document 3), the PEG hemoglobin having polyethylene glycol) (PEG) as a water soluble polymer bound to the molecular surface of human hemoglobin (e.g., see Patent Document 4), and the like have been developed, and the clinical studies have progressed. While these artificial oxygen carriers have a molecular design to avoid renal excretion due to disassociation to a subunit of hemoglobin and the like by crosslinking between subunits or increasing the molecular size (molecular weight), no formulation approved by Food and Drug Administration (FDA) and clinically used yet exists, for reasons that in the clinical study, a side effect such as increased blood pressure due to vasoconstriction occurs, no difference in effect is seen between the artificial oxygen carrier administration group and the saline administration group, and the like.
On the other hand, in Japan, development of a cellular type artificial oxygen carrier having hemoglobin encapsulated in the internal water phase of bilayer membrane vesicle (liposome) formed by self-organization of a phospholipid molecule in water has also progressed (e.g., see Patent Document 5). Although this cellular type artificial oxygen carrier does not have any problematic side effect and its practical application has been desired, it has not reached the clinical study, due to the problem that high preparation technology and initial cost are required.
Moreover, the inventors have focused on the multimolecular binding capacity of serum albumin contained in blood in a second larger amount to hemoglobin among protein, and developed an albumin-heme complex having iron porphyrin (heme) to be an oxygen binding site included in the hydrophobic pocket thereof (e.g., see Patent Document 6). Although it is clear that this albumin-heme complex has an oxygen binding capacity and an in vivo oxygen transport capacity, there are problems that the synthesis is complicated due to the special structure of a heme derivative, stability of the oxygenated form of a heme derivative is lower than stability of the oxygenated form of hemoglobin, and the like.
From the above background, development of a novel artificial oxygen carrier which has high stability of the oxygenated form, has high biocompatibility (e.g., no renal excretion, no side effect such as increased blood pressure), and is easily prepared (synthesized), has been strongly desired.